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					                                                                                      Iran J Pediatr
 Case Report                                                               Dec 2007; Vol 17 ( No 3), Pp:388-392

                   Menkes Disease: Report of Two Cases

             Mohammad Barzegar*1, MD; Afshin Fayyazie1, MD; Bobollah Gasemie2, MD;
                             Mohammad ali Mohajel Shoja3, MD

      1. Pediatric Neurologist, Department of Pediatrics, Tabriz University of Medical Sciences, IR Iran
      2. Pathologist, Department of Pathology, Tabriz University of Medical Sciences, IR Iran
      3. General Physician, Tabriz University of Medical Sciences, IR Iran

                          Received: 14/05/07; Revised: 20/08/07; Accepted: 10/10/07

   Introduction: Menkes disease is a rare X-linked recessive disorder of copper metabolism. It is
   characterized by progressive cerebral degeneration with psychomotor deterioration, hypothermia,
   seizures and characteristic facial appearance with hair abnormalities.
   Case Presentation: We report on two cases of classical Menkes disease with typical history,
   (progressive psychomotor deterioration and seizures}, clinical manifestations (cherubic appearance,
   with brittle, scattered and hypopigmented scalp hairs), and progression. Light microscopic
   examination of the hair demonstrated the pili torti pattern. The low serum copper content and
   ceruloplasmin confirmed the diagnosis.
   Conclusion: Menkes disease is an under-diagnosed entity, being familiar with its manifestation and
   maintaining high index of suspicion are necessary for early diagnosis.

  Key Words: Menkes disease, Copper metabolism, Epilepsy, Pili torti, Cerebral degeneration

                                                             colorless. Examination under microscope reveals
Menkes disease (MD), also referred to as kinky               a variety of abnormalities, most often pili torti
hair disease, trichopoliodystrophy, and steely hair          (twisted hair), monilethrix (varying diameter of
disease, is a rare X-linked recessive disorder of            hair shafts) and trichorrhexis nodosa (fractures of
copper metabolism.[1,2] It is characterized by               the hair shaft at regular intervals)[4]. The clinical
progressive cerebral degeneration with psycho-               picture is caused by a defect in copper
motor deterioration, seizures, and connective                transporting ATPase (ATP7A), resulting in
tissue alteration with hair abnormalities.[2,3] The          defects of key copper dependent enzymes,
most striking finding is the appearance of the               including lysyl oxydase, cytochrome c oxidase,
scalp hair, being thin, coarse, brittle and                  dopamine β-hydroxylase, tyrosinase, and super

* Correspondence author;
Address: Pediatric Department, Tabriz Children Hospital, Sheshgelan St, Tabriz, IR Iran
Iran J Pediatr. Vol 17 (No 4); Dec 2007                                                                       389

oxide dismutase. Depigmentation of hair and skin         control. Light microscopic examination of the
pallor are due to tyrosinase deficiency,                 scalp hair showed pili torti. The diagnosis of MD
hypothermia is due to cytochrome c oxidase               was confirmed on the basis of low serum copper
deficiency and lysyl oxidase deficiency causes           (15 μg/dl; ref. range: 70-150 μg/dl) and low
tortuous arteries in brain, progressive vascular         serum ceruloplasmin (58 mg/l; ref. range: 187-
changes predispose to thrombosis and deficient           322, mg/l). There were no abnormalities in other
blood supply to the developing brain[2,3,5].             standard blood analyses. The electroencephalo-
Neuroimaging discloses atrophy and bilateral             graphy showed multifocal spikes and waves with
ischemic lesions in deep gray matter or in the           poorly organized sleep features. Brain CT scan
cortical areas; the consequence of vascular              demonstrated cerebral atrophy and subdural
infarctions.[7]                                          effusion. Copper-histidine was prescribed.
    Management of patients with MD is                    Despite anticonvulsant therapy with various
supportive, with an emphasis on anticonvulsant           drugs (phenobarbital, clonazepam, nitrazepam,
treatment and a trial of copper histidine therapy.       vigabatrin) intractable seizures continued. At the
Prognosis is poor with progressive neurological          end of the first year of life, neurological
deterioration and eventual death within the first 3      milestones such as head control, rollover
years of life.[3]                                        response and laughing had not been achieved.
    The clinical history and the appearance of the       Unfortunately, the patient died of a respiratory
infant should suggest the diagnosis. Microscopic         infection at the age of 14 months.
examination of the hair is very helpful even in a
mild case. Low levels of serum copper and
ceruloplasmin will usually confirm the
diagnosis.[5] If doubt still exists, the diagnosis can
be confirmed by demonstrating the intracellular
accumulation of copper and decreased efflux of
   Cu from cultured fibroblasts.[6] Menkes disease
is a rare disorder; its frequency has been
estimated 1 in 114000-250000 live births.[8]
    We report on two cases of classic MD
diagnosed in Tabriz Children's Hospital, a
university- affiliated tertiary hospital in the East
Azarbaijan province, the North West of Iran
between years 2002 and 2006.
                                                          Fig 1- Scattered and hypopigmented scalp hairs
                                                                         in Menkes disease

Case(s) Presentation                                     Case 2: The five month-old male infant was
                                                         referred to our hospital with regression of
Case 1: A seven month-old male infant was                developmental milestones and seizures. He was
brought to our out-patient clinic due to gradual-        born at term to healthy consanguineous parents.
onset of hypotonia and seizures. The boy was             The pregnancy was uneventful. At birth the head
born at 34 weeks of gestational age to healthy,          circumference and body weight were 35 cm and
non-consanguineous parents. He was the first             3.2 kg, respectively. Family history was
child of the parents. His early development was          remarkable for the death of two previous male
age appropriate for 3 months, and then regressed.        siblings at the age of 1 month and 18 months.
At 5 months of age myoclonic jerks were noted.           They had severe neurodevelopmental delay
His clinical examination at 7 months revealed            without a definite diagnosis. The patient had a
cherubic appearance with depressed nasal bridge,         history of 8 days hospital admission on third day
and brittle, scattered and hypopigmented scalp           of life with poor feeding, hypothermia and
hairs (Fig 1). He had no eye contact and no head         hyperbilirubinemia (total bilirubin was 16 mg/dl).
390                                                                               Menkes Disease. M Barzegar, et al

      His early development was age appropriate for 4       seizures and failure to thrive. Cerebral
      months, at 3 months of age he had good head           degeneration then dominates the clinical
      control and laughing. At 4 months of age tonic        picture.[1,3,5]
      and myoclonic seizures were noted. On clinical            Children often have a cherubic appearance
      examination at 5 months, the most striking            with sparse, course, short, twisted, and lightly
      finding was the appearance of the scalp hair. It      pigmented hair. Individuals with the mild variant
      was colorless, thin, brittle and kinky. Although      are developmentally delayed with cerebellar
      eye contact was noted, he had poor head control       ataxia, dysarthria and pili torti, and no seizures.
      and no rollover response. Brain CT scan showed        The occipital horn syndrome is considered a MD
      cerebral atrophy and subdural effusion. An            variant. The skeletal dysplasia, soft bruisable
      electroencephalography       revealed      frequent   skin, hyper-extensible joints, diarrhea, and
      multifocal     epileptiform     discharges     with   occipital exostosis characterize it.[12]
      disorganized background. With high suspicion of           The typical history and clinical features in our
      MD, serum copper and ceruloplasmin were               patients were suggestive of classical MD. The
      determined; with 3 μg/dl (ref. 70-155) and 15         cherubic facial appearance with a depressed nasal
      mg/l (ref. 187-320 mg/l) respectively both were       bridge in both of them was similar to reported
      below normal levels. Light microscopic                cases in the past.[1-3,5,6,9,13]
      examination of the hair showed pili torti (twisted        Hair abormalities are the most striking signs
      hair shafts) and trichorrhexis nodosa. There were     in this syndrome. Our patients showed brittle,
      no metaphyseal changes of long bones on X-rays.       scattered and hypopigmented scalp hairs; under
      There were also no abnormalities in other             microscope hair was shown to be twisted
      standard blood analyses. The diagnosis of MD          longitudinally with narrowing at intervals along-
      was made. Phenobarbital and nitrazepam were           with many erosions on the hair shaft. The hair
      partially effective. Poor weight gain, seizures and   was fragile and fractured easily, resulting in
      neurologic deterioration were evident in a visit at   apparent generalized alopecia. Several hair shaft
      1 year of age. At 17 months of age he showed          abnormalities have been documented, with pili
      severe global developmental delay and failure to      torti being the most common, also trichorrehexis
      thrive. He has had two short hospital admissions      nodosa, trichoclasis, and trichoptilosis have been
      for chest infection and diarrhea.                     reported.[4,14] The scalp hair may appear normal
                                                            at birth, but at approximately three months of age
                                                            the hair on the scalp and eyebrows becomes
                                                            kinky, coarse, and lightens in color.[1,3,5]
      Discussion                                                Non–skin manifestations in our patients were
                                                            delayed developmental milestones and intractable
      The clinical features and inheritance of MD were      seizures similar to other reports.[1,3,5,6,9] Epilepsy
      first described in 1962.[9] Ten years later the       is a frequent and early feature in MD, it was
      underlying biochemical defect in copper               reported in our cases. Myoclonous is the usual
      metabolism was discovered.[10] The clinical           seizure type; other types of seizures, including
      spectrum of MD encompasses several distinct           multifocal seizure and tonic spasms are also
      variants. The neonatal form is characterized by       reported. Seizures are usually resistant to
      multiple fractures and extensive vascular disease     antiepileptic drugs. The pathophysiologic
      with early death[11]. Infants with classic MD         mechanisms of epilepsy in MD remain unknown,
      typically appear healthy until 2 to 3 months of       but they are likely related to copper deficiency. It
      age. Premature delivery is very frequent, as are      results in an impairment of lysyl oxidase,
      neonatal hypothermia and hyperbilirubinemia.          considered as the primary cause of the abnormal
      Hypothermia may also occur in older infants.          intracranial vessel structures.[15]
      Neonatal symptoms may resolve, and the babies             Our patients had low serum copper and
      may seem normal during next 2 or 3 months. At         ceruloplasmin levels which correlated with the
      3 months of age they start to demonstrate             clinical findings, these levels are usually low but
      developmental delay, hypotonia, intractable           interpretation may be difficult in the first few
Iran J Pediatr. Vol 17 (No 4); Dec 2007                                                                      391

months of life[5]. In the past, the final diagnosis     References
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                                                          11. Jankov RP, Boerkoel CF, Hellmann J, et
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                                                              al. Lethal neonatal Menkes disease with
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                                                              severe vasculopathy and fractures. Acta
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                                                              Paediatr. 1998;87(12):1297-300.
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